HIV (Human Immunodeficiency Virus) Essay Example for Free

HIV (Human Immunodeficiency Virus) Essay HIV (Human Immunodeficiency Virus) causes AIDS (Acquired Immune Deficiency Syndrome) that disables the immune system.  It was discovered in 1983 .HIV enters the body through the bloodstream and duplicates itself rapidly.  The victim is susceptible to infectious diseases that eventually are fatal (1). Statistically, HIV/AIDS is the number one killer of African-American women ages 25 to 34, according to the Centers for Disease Control and Prevention.  Between 2000 and 2003, they were nineteen times more likely than White females and five times more likely than Hispanic females to contract the disease.   African-American men were seven times more likely than White men and three times the rate of Hispanic men to contract HIV/AIDS (2). In 2008, there is still not a cure for AIDS.  Instead, scientists have discovered drugs that can slow down the progression of the disease. Protease inhibitors (PIs) are antiviral drugs that slow down the spread of HIV (1). The virus produces a protein called protease so that it can replicate itself.  Ã¢â‚¬Å"Protease cuts long chains of proteins and enzymes into shorter chains, the first step in the process by which HIV infects a cell† (1).  If this doesn’t happen, replication does not continue. In 1987, AZT was the first anti-HIV medication that was created.   It showed hope and kept people healthier longer.   However, the side effects were very high for men.   Since that time, more HIV medications have evolved.   Antiretroviral therapy usually consists of combinations of nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or fusion inhibitors, which are prescribed in the later stages of HIV (19). Dual protease inhibitor therapy is also being used clinically (3).  They are also associated with improving morbidity and mortality of HIV-positive persons (5).  Although these drugs are expensive, they have proven to be the most successful therapy in managing HIV.   However, some patients don’t comply 100% with their treatments.   This is largely due to the side effects. Sometimes they make a patient feel worse than the actual disease. The most commonly reported ones are abdominal pain, abnormal bowel movements, diarrhea, fatigue, headache, and nausea.   Children usually develop a skin rash. The more serious side effects are liver problems and pancreatitis.   Some patients have also seen large increase in triglyceride ad cholesterol levels.   Diabetics saw an increase in their blood sugar levels.   Other patients developed diabetes while taking protease inhibitors (16). Presently, nine PIs have been approved for use in the United States and Europe:   amprenavir, atazanavir, fosamprenavir, lopinavir, indinavir, ritonavir, saquinavir, tipranavir, and nelfinavir. Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used for treatment of HIV:  nevirapine, delavirdine, and efavirenz (7). Drug treatment selection depends on factors such as drug resistance, tolerability, drug interactions, and effectiveness. Therapeutic drug monitoring (TDM) â€Å"has been proposed so that practitioners may better maintain appropriate plasma concentrations of drugs in their patients by identifying interactions with other medications and assessing medication adherence   (7). Figure 1 shows the structures of these compounds. Fig. 1. Chemical structures of protease inhibitors and non-nucleoside reverse transcriptase inhibitors. About 50% of â€Å"treatment-naà ¯ve patients† don’t have continued antiviral response after one year of therapy (18). In some cases, there is a development of drug resistance and metabolic complications.   Also, â€Å"there is increasing evidence that virological treatment failure is correlated with variations in the pharmacokinetic parameters of drugs (20).   This can be due to drug interactions, low bioavailability, and variations in metabolic enzyme activity.   Atazanavir (ATV) has good oral bioavailability and a favorable pharmacokinetics profile (18).   With this in mind, patients can mostly take a once-daily dose. A separate analytical method has been recently published for quantifying ATV in human plasma using solid phase extraction and HPLC with PDA (photodiode array) detection at 201 nm (18).   This method provides excellent separation of ATV from its internal standard, clozapine (CLZ) and the other PIs, thus, obtaining an accurate measurement of the drug (see figure 2). CLZ elutes at 8.9 minutes, and ATV elutes a 24.4 minutes. A 40-ml injection resulted in a recovery yield of 100%. Fig. 2.   Chromatogram of ATV with PIs/NNRTIs (8000 ng/ml) spiked with CLZ Nelfinavir mesylate has been shown in phase III controlled clinical trials to significantly reduce viral load and increase CD4+ cell counts when used with reverse transcriptase inhibitors. It’s prescribed as part of triple drug combination therapy (9). CD4+ are helper T cells.   They are important for immune reconstitution in patients that are receiving antiretroviral therapy (10).   After a large number of these cells are destroyed, AIDS develops (7). Six clinical trials was conducted in the past ten years using 2, 148 HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group treatment trials (10).   Patient ages varied from 2 to 7 years of age.   The focus was to observe short-term variability of CD4 percentages.   The study found that 49% of patients had CD4 percentages above 25%.   32% of patients had CD4 counts between 15% and 24%; 19% were less than 15%.   Finally, 5.4% had a CD4% of less than 5% (10). In June 2006, Darunavir (DRV) was licensed in the United States.   It is a promising PI that is active against HIV strains that are resistant to the other PIs that currently on the market (17).   It is prescribed in 600-mg doses that are taken twice daily with 100 mg of ritonavir that acts as a booster. Protease inhibitors are associated with unfavorable pharmacokinetics and many side effects such as gastrointestinal disturbances and lipid abnormalities (5).  Four of the most common PIs used are indinavir, ritonavir, saquinavir, and nelfinavir (3).  Ã¢â‚¬Å"Monitoring blood concentration of PIs, which can indicate both therapeutic and toxic levels of the drugs as well as patient noncompliance with the medication, may improve the care of both HIV-infected adults and children† (3). When ritonavir was first introduced, it was given in doses of 600 mg every 12 hours. â€Å"However, patient intolerance of full doses led to its primary use as a pharmacologic enhancer to increase the concentrations in plasma of a second protease inhibitor to improve the convenience of antiretroviral regimens by extending the dosing interval, reducing pill burden, and /or eliminating food-induced reductions in pharmacokinetic exposure† (8).   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Researchers used High Performance Liquid Chromatography (HPLC) to determine concentrations of PIs in blood.  Various methods have been used to study the pharmacokinetics and drug interactions. Interpreting plasma levels can be used to â€Å"individualize drug dosage of antiretrovirals (4). Quality control (QC) procedures must be done to ensure that these methods are accurate and precise.  Ã¢â‚¬Å"Such procedures usually include intralaboratory (internal) method validation, intralaboratory QC procedures, and participation in an interlaboratory QC program for antiretroviral drugs† (4). Since the latter hadn’t been done before, it was established so that laboratories can obtain better measurement results of antiretroviral drugs. Nine laboratories participated in the first part of the program.  The first part of the experiment involved the measurement of the protease inhibitors:  indinavir, nelfinavir, ritonavir, and saquinavir.  All had a specified purity of 99% or higher.  QC samples were prepared by spiking blank plasma from HIV-negative volunteers with PI standard. The low concentrated standards ranged from 0.087 to 0.15 mg/L while the intermediate concentrated standards contained ranged from 2 to 3 mg/L of all four PIs.  Finally, the high-concentrated standards contained approximately 5 to 11 mg/L of drug.  All drugs were dissolved in methanol following accurate weighings and diluted with blank plasma (4). High Performance Liquid Chromatography (HPLC) was used to analyze twelve samples.  All laboratories measuring more than one protease inhibitor used as assay for â€Å"simultaneous determination† (4).  Six laboratories used HPLC/UV and three labs used HPLC-MS/MS. Mass spectrometry detection is often recommended for measurement of low concentration levels.  Also, this type of analysis is usually faster and â€Å"does not require complete resolution of drugs for detection and quantification† (5).  Only five laboratories were able to measure all four PIs.  Three laboratories were not able to determine nelfinavir.  One laboratory only measured indinavir (4). Acceptable accuracy results are between 80% and 120%.  Only indinavir resulted in an acceptable accuracy of 80%.  The remaining PIs had between 36% and 74% accuracy.  These results should encourage laboratories to improve their analytical methods and QC procedures.  Other PIs, such as amprenavir and lopinavir, can be analyzed as well (4). HIV-positive plasma samples are heat inactivated before analysis, approximately 58 °C for 40 minutes, to decrease the risk of infection to the operator.  They may also go through a freeze/thaw cycle. As with the QC study, blank plasma was spiked with seven PIs (indinavir, amprenavir, atazanavir, ritonavir, saquinavir, lopinavir, and nelfnavir) at low, intermediate, and high concentrations measured in ng/ml.  Certain assays only require 100  µl of plasma for analysis.  Ã¢â‚¬Å"This is advantageous when measuring PI concentrations as part of clinical studies as they often necessitate hourly sampling to generate complete PK profiles; therefore less blood can be drawn from the patient† (5).  In addition, seven PIs can be quantified in one assay, but impossible to assay all seven in a single preparation. â€Å"The use of liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) has emerged as the developmental method of choice supporting clinical and pre-clinical pharmacokinetic studies† (13). Recovery for the HPLC-MS/MS methods was above 87% for all seven drugs at all three concentration levels (5).  It was successful in quantifying seven PI concentrations in plasma of HIV positive persons that participated in a run time of nine minutes.  Therefore, the assay may be used for determining PI concentrations in semen, lymphocytes, and cerebrospinal fluid (5). A fast and highly-sensitive LC-MS-MS method was developed that could analyze five protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) in one run using an internal standard.   Sample sizes were small (ng/ml) and run times were approximately 5 minutes.   Recoveries for all five PIs were between 87% and 92%(11). Tipranavir is part of a class of non-peptidic PIs that works against both â€Å"wild-type virus and variants resistant to current PIs†(6).  It also has a high genetic barrier.  Tipranavir is prescribed in a 500-mg dose taken in combination with 200 mg of ritonavir twice daily as part of antiretroviral therapy for patients with HIV-1 strains that are resistant to multiple PIs (6). Fig. 3. Tipranavir chemical structure   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  An HPLC-UV method has been validated and is currently applied when monitoring tipranavir (TPV) plasma levels in HIV patients.  Samples were prepared for solid phase extraction (SPE) by conditioning the cartridges with 0.1% phosphoric acid, pH 7.  TPV stock solutions with a concentration of 5 mg/ml were diluted from with 50% methanol. Samples were spiked with TPV at 1.875, 7.5, 18.75, 37.5, 60, and 75  µg/ml in triplicate. QC samples were diluted with blank plasma and phosphate buffer to 5.625, 22.5, and 67.5  µg/ml.  Clozapine was used as the internal standard (6).  5-ml aliquots of blood samples were obtained from HIV infected patients.  The plasma obtained from centrifugation was heated at 60 ° C for one hour in a water bath. TPV in plasma was measured at a UV absorbance of 201 nm with a retention time of 32.2 minutes. Its internal standard, clozapine (CLZ) has a retention time of 8.3 minutes (6). Figure 4 below shows the chromatogram of TPV, its internal standard, and all other PIs and NNRTIs  present.   Figure 5 shows TPV and its internal standard CLZ only. Fig. 4. Chromatogram of plasma control sample of TVP (22.5 mg/ml) spiked with internal standard and all PIs and NNRTIs. Fig. 5. Chromatogram of calibration sample of TVP (37.5 mg/ml) spiked with internal standard CLZ. Isocratic HPLC methods combined with the use of UV and fluorescence detection produces more sensitivity. Amprenavir is a fluorescent compound.   Its internal standard PR25 can also be seen under fluorescence (see figure 6). Fig. 6.   Blank plasma with 100 ng/ml amprenavir and 1000 ng/ml of PR25 seen under fluorescence. In conclusion, much progress has been made in the development of protease inhibitors and other antiretroviral therapy. HPLC with UV detection has been the most commonly used method of analysis.   It is rapid, simple, and highly sensitive.   LC-MS-MS has been noted at the developmental method of choice for clinical and pre-clinical pharmacokinetic studies (13).   More compounds can be analyzed in less time.   Also, they can be used for methods using other human biological matrices. For the majority of protease inhibitors, all side effects are not known. In 2007, darunavir was the new HIV protease inhibitor with eleven other antiretroviral agents on the market.   They can affect patients that have diabetes, liver problems, and hemophilia; their conditions can worsen as a result of taking PIs. Only a patient’s health care provider can determine the best treatment option REFERENCES Nagel, Rob. 2007. Protease Inhibitors. UXL Encyclopedia of Science; [cited 2008 May 8], Available from http://galenet.galegroup.com/servlet/SciRC?ste=1docnum=cv2644301082. Health Hotline:   HIV and Genital Herpes [cited 2008 May8]; Available from http://www.ebony.com. â€Å"HPLC Assay for Common Protease Inhibitors Developed.†Antiviral Weekly; [cited 2008 May 07; Available from http://galenet.galegroup.com/servlet/SciRC?ste=1docNum=A60069570. Aarnoutse, Rob E., Verweij-van Wissen, Corrien P.W.G.M., van Ewijk-Beneken Kolmer, Eleonora, W.J., Wuis, Eveline, W., Koopmans, Peter P., Hekster, Yechiel A., and Burger, David, M. 2001. International Interlaboratory Quality Control Program for Measurement of Antiretroviral Drugs in Plasma; Antimicrobial Agents and Chemo 46(3): 884-886. Dickinson, Laura, Robinson, Lesley, Tjia, John, Khoo, and Saye, Back, David. 2005. Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir in human plasma by high-performance liquid chromatography-tandem mass spectrometry; J of Chrom. B 829:82-90. Colombo, S., Beguin, A., Marzolini, C., Telenti, A., Biollaz, J., and Decosterd, L.A. 2006.   Determination of the novel non-peptidic HIV-protease inhibitor tipranavir by HPLC-UV after solid-phase extraction; J of Chrom. B 832:138-143. Rezk, Naser L., Tidwell, Richard R., and Kashuba, Angela D.M. 2004.   High-performance liquid chromatography assay for the quantification of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in human plasma; J of Chrom. B 805:241-247. Shelton, Mark J.,Hewitt, Ross G., Adams, John, Dela-Coletta, Andrew, Cox, Steven, and Morse, Gene D. 2003. Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients; Antimicrobial Agents and Chemo 47(5): 1694-1699. Zhang, Kanyin E., Wu, Ellen, Patick, Amy K., Kerr, Bradley, Zorbas, Mark, Lankford, Angela, Kobayashi, Takuo, Maeda, Yuki, Shetty, Bhasker, and Webber, Stephanie. 2001.Circulating Metabolites of the Human Immunodeficiency Virus protease Inhibitor Nelfinavir in Humans:   Structural Identification, Levels in Plasma, and Antiviral Activities; Antimicrobial Agents and Chemo 45(4): 1086-1093. Carey, Vincent J., Pahwa, Savita, and Weinberg, Adriana. 2005.   Reliability of CD4 Quantitation in Human Immunodeficiency Virus-Positive Children:   Implications for Definition of Immunologic Response to Highly Active Antiretroviral Therapy; Clinical and Diagnostic Lab Immunology 12(5): 640-643. Chi, Jingduan, Jayewardene, Anura L., Stone, Judith A., Motoya, Toshiro, and Aweeka, Francesca. 2002.   Simultaneous determination of five HIV protease inhibitors nelfinavir, indinavir, ritonavir, saquinavir and amprenavir in human plasma by LC/MS/MS; J of Pharm and Biomedical Analysis 30:675-684. Verbesselt, R., Van Wijngaerden, E., and de Hoon, J. 2007. Simultaneous determination of 8 HIV protease inhibitors in human plasma by isocratic high-performance liquid chromatography with combined use of UV and fluorescence detection: Amprenavir, indinavir, atazanavir, ritonavir, lopinavir, saquinavir, nelfinavir and M8-nelfinavir metabolite; J of Chrom. B 845:51-60. Frerichs, Valerie A., DiFrancesco, Robin, and Morse, Gene D. 2003. Determination of protease inhibitors using liquid chromatography-tandem mass spectrometry; J of Chrom, B 787:393-403. Gangl, Eric, Utkin, Ilya, Gerber, Nicholas, and Vouros, Paul. 2002. Structural elucidation of metabolites of ritonavir and indinavir by liquid chromatography-mass spectrometry; J. of Chrom. A 974:91-101. Turner, Michele L., Reed-Walker, Kedria, King, Jennifer R., and Acosta, Edward P. 2003. Simultaneous determination of nine antiretroviral compounds in human plasma using liquid chromatography; J. of Chrom. B 784:331-341. 2008. Kaletra. [Cited 2008 May 16], Available from http://www.heartandsoul.com. D’Avolio, Antonio, Siccardi, Marco, Sciandra, Mauro, Lorena, Baietto, Bonora, Stefano, Trentini, Laura, and Di Perri, Giovanni.2007. HPLC-MS method for the simultaneous quantification of the new HIV protease inhibitor darunavir, and 11 other antiretroviral agents in plasma of HIV-infected patients; J. of Chrom. B 859:234-240. Colombo, S., Guignard, N., Marzolini, C., Telenti, A., Biollaz, J., and Decosterd, L.A. 2004. Determination of the new HIV-protease inhibitor atazanavir by liquid chromatography after solid-phase extraction; J. of Chrom. B 810:25-34. Weller, Dennis R., Brundage, Richard C., Balfour, Jr., Henry H., and Vezina, Heather E. An isocratic liquid chromatography method for determining HIV non-nucleoside reverse transcriptase inhibitor and protease inhibitor concentrations in human plasma; J. of Chrom. B 848:369-373. Sarasa-Nacenta, Maria, Lopez-Pua, Yolanda, Mallolas, Josep, Blanco, Jose’ Luis, Gatell, Jose’ M., and Carne’, Xavier. Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high- performance liquid chromatography; J, of Chrom. B 757:325-332.

Compare and Contrast The Day After Tomorrow and Outbreak Essay

Which of these movies provides a more effective wake-up call about impending global catastrophes? â€Å"The Day After Tomorrow† and â€Å"Outbreak† both raise important concerns regarding the world that we live in. The first movie seems to serve mainly as a warning that as a people of this planet we need to do everything in our power to stop destroying our world. â€Å"Outbreak† demonstrates the vulnerability of the United States and for that matter all nations of the world in dealing with large epidemics. Though both movies raise legitimate concerns they also both are quite sensationalized in order spice it up for moviegoers. The most effective movie in providing a wake up call for humanity is totally debatable and is entirely dependent on the eye of the beholder. In â€Å"The Day After Tomorrow† a climatologist’s warning of the possibility of massive cataclysmic climate changes caused by global warming go unheeded. His predictions of the consequences of such actions just so happen to occur sooner than anyone had ever expected. This movie served as the ultimate example what could happen if as a world community we do not clean up our acts. Continued consumption of nonrenewable resources, increased carbon dioxide emissions and further depletion of the Ozone layer could though most likely not on the scale illustrated occur in one form or another. The moral of this film is summed up by Dennis Quaid’s character in the last scene when he mutters his last few lines stating that hopefully humani...

Swot Dropbox

Strengths: first one to have the idea of cloud storage with synchronization, accessible where you want from any devices, simple design easy to use, exactly same data everywhere you go principle of synchronization, saved in dropbox. com if your laptop is out of use you have access to your files online, enable multi-users to share files, revision-history button to recover deleted files, 2GB storage for free to attract the consumers, pop up if you connect a usb stick or SD card to your computer â€Å"do you want to synchronize these files with Dropbox, turn loyal customer into salesperson: 250MB for free if referral (1/4 of Dropbox users come this way), no files capacity transfert limitation.Weaknesses: need access to internet to download Dropbox, 2GB limited storage for free (competition eg amazon offers 5GB for free as already mentioned by Janine), you cannot store more than the available place on your device, dealing with paid search advertisement, security problem in 2011.Opportuni ties: engagement on social media, deal with HTC to be default cloud storage on Androids, talking about it with 6 other phone firms then PC and TV, E marketing benefits: control, reach, interactivity.Threats: competitors such as Google or Apple could overtake the leader position in B2C market, competition offers lower prices, if Dropbox does not implement himself better in the enterprise market they could loose market shares of B2C market because it has been proven that home market copies enterprise market, possibility of cloud back up system being attacked by external or internal users ? introduction of a spyware through Dropbox

Plus ça Change - French Expression

Expression: Plus à §a change, plus cest la mà ªme chose Pronunciation: [plu sa sha(n)zh plu say la mem shoz] Meaning: the more things change, the more they stay the same. Literal translation: more it changes, more its the same thing. Register: normal How to Use Plus à §a Change The pessimistic French expression plus à §a change, plus cest la mà ªme chose is very often cut down to just the first clause: plus à §a change... / the more things change... The shortened French expression is often used in English too, particularly British English.In either language, plus à §a change indicates a certain disillusionment or resignation regarding whatever is being talked about. A company makes all kinds of policy changes, for example, but the personnel issues are unaffected. A couple go to marriage counseling, but continue fighting about everything. A new sheriff comes to town, but there is no noticeable impact on crime. New people, new promises, but the same old problems - plus à §a change.... Variations: Plus à §a change, plus cest pareil: The more it changes, the more its the same.Plus à §a change (et) moins à §a change: The more it changes (and) the less it changes